The majority of adult smokers initiate smoking as children. Most previous studies of the biological effects of nicotine have focused on adults rather on adolescence, a developmental period that is characterized by sexual maturation and by significant changes in brain structure and function. In the present proposal we will use animal models to examine the biological factors that underlie susceptibility to nicotine. In particular, we will test the following hypotheses: (l) That the balance of reinforcing/aversive effects of nicotine is greater in juveniles than in adults. (2) That individual differences in susceptibility to nicotine dependence are associated with variations in stress responsivity. Three specific aims are proposed. First, the effects of nicotine will be compared in juvenile rats aged postnatal day (p) 30 and in adults. Animals will be treated with nicotine and tested behaviorally. At the end Of some experiments animals will be decapitated and trunk blood collected for the measurement of corticosterone levels. Brains will be processed by in situ hybridization for quantitative analysis of the expression of mRNA for the immediate early gene, cfos, in specific neuronal populations. Experiments will be conducted with both male and female rats to determine whether nicotine is more reinforcing in juveniles than adults using both conditioned place preference and self adrnistration paradigms. Animals will also be tested to determine whether conditioned sensitization to the locomotor activating effects of nicotine Occurs more rapidly in juveniles than adults, and to determine whether juvenile exposure to nicotine increases sensitivity to nicotine in adults. Second, individual differences in stress responsivity will be induced by a procedure in which pups are either handled (H) or not handled (NH) for two weeks after birth. H and NH groups will then be compared as juveniles and adults to determine whether differences in stress responsivity result in different acute effects of nicotine on locomotion, plasma corticosterone and cfos expression. Differences in the reinforcing effects of nicotine in H and NH groups will also be examined, as will differences in withdrawal severity following chronic nicotine treatment. Third, the effects of nicotine on genetically distinct strains of mice will be studied. Both acute and chronic effects of nicotine in C3H andC57B1/6J mice, and in transgenic mice with alterations in selected genes, will be examined. These studies will provide critical information on the biological mechanisms underlying individual variations in responsivity to nicotine and will complement the human studies in projects I and 2.